This application is a 371 of PCT/FR00/00672 filed Mar. 17, 2000, now WO00/55160 Sep. 21, 2000.
The present invention relates to pharmaceutical composition based on polyaromatic compounds which are useful in particular as antitumor medicinal products.
In 1999, the cytotoxic treatments (chemotherapy) used to reduce the size of cancer tumors, to contain the development of the tumoral process or even, in all too few cases, to eliminate lumps of cancer cells and the risk of metastases, combine chemical substances recently introduced with others which have been used for a few decades. For example, 5-fluorouracil (5-FU), which has been known for nearly 40 years as one of the most active treatments for colorectal cancer, may be replaced with one or other of the inhibitors specific for topoisomerase I (irinotecan or topotecan) when the tumor is no longer sensitive to 5-FU. More generally, the therapeutic arsenal available for treating colorectal cancers is also enriched by the availability of oxaliplatin, novel in situ xe2x80x9cdonorsxe2x80x9d of 5-FU or selective inhibitors of thymidylate synthase. This co-existence is not limited to the treatment of colorectal cancers since, in addition, the chemotherapy of breast, ovarian and lung cancers now makes wide use of the family of taxane derivatives (paclitaxel and docetaxel). The need for more effective and better-tolerated treatments, thus improving the survival and quality of life of the patients, is imperative since, again taking the example of colorectal tumors, it has been estimated (S. L. Parker, T. Tong, S. Bolden et al., CA Cancer J. Clin., 1997) that, in the United States alone, more than 131 000 new cases were diagnosed in 1997, of which 54 000 were responsible for the death of the patients. It is the awareness of this situation which has incited the inventors to focus their attention on a family of polyaromatic compounds that have as yet been little studied, identified in Ascidians of warm seas, to develop a novel medicinal chemistry intended to select synthetic compounds derived from chemical design/modulation research and endowed with significant therapeutic cytotoxic activity.
The seas and oceans which cover more than 70% of the world""s surface are home to marine plants and sponges whose progressive systematic pharmacognosic study shows that these living species may contain complex alkaloids with advantageous pharmacological properties. For example, the sponges Cryptotheca crypta and Halichondria okadai have been the subject of in-depth research since the discovery of the presence, in their cells, of cytarabin or of halichondrin B. This is likewise the case for the family of tunicates, since the isolation of aplidin from the tunicate Aplidium albicans which lives in the Balearic islands (Spain) Alkaloids of tetrahydroisoquinolone structure have been isolated from the ascidian Ecteinascidia turbinata. Among these, ecteinascidin-743 has been the subject of in-depth preclinical studies (E. Igbicka et al., NCI-EORTC symposium, 1998; Abst. 130 p. 34), and also of clinical tests intended to define its therapeutic potential as an anticancer medicinal product (A. Bowman et al., NCI-EORTC symposium, 1998; Abst. 452 p. 118; M. Villanova-Calero et al., NCI-EORTC symposium, 1998; Abst. 453 p. 118; M. J. X. Hillebrand et al., NCI-EORTC symposium, 1998; Abst. 455 p. 119; E. Citkovic et al., NCI-EORTC symposium, 1998; Abst. 456 p. 119). Novel pentacyclic acridine derivatives have also formed the subject of pharmacochemical studies (D. J. Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).
Among these compounds, mention may be made of meridine, an natural alkaloid extracted from the ascidian Amphicarpa meridiana or from the marine sponge Corticum sp. Meridine was isolated by Schmitz et al. (J. Org. Chem. 1991; 56: 804-808) and then described for its antiproliferative properties on a model of murine leukemia (P388) and its antifungal properties in patent U.S. Pat. No. 5,182,287 (Gunawardana et al. of Jan. 23, 1993). Its antifungal properties were described by McCarthy et al. (J. of Nat. Products 1992; 55: 1664-1668) along with its cytotoxic properties on two human cell lines: colon cancer cells (HT-29) and lung carcinoma cells (A549), which were reported by Longley et al. (J. of Nat. Products 1993; 56: 915-920). The synthesis of meridine has been carried out according to various processes by Kitahara et al. (Chem. Pharm. Bull 1994; 42: 1363-1364), Bontemps et al. (Tetrahedron 1997; 37: 1743-1750) and Kitahara et al. (Tetrahedron 1998; 54: 8421-8432).
Among these compounds, mention may also be made of cystodamine, a pentacyclic alkaloid isolated from the Ascidian Cystodytes dellechiajei by Bontemps et al. (Tetrahedron lett., 1994; 35: 7023-7026) which has activity on human leukemia lymphoblasts.
The subject of the present invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formulae: 
in which:
R1, R3, R4, R5 and R6 are chosen from hydrogen, halogens and hydroxyl, xe2x80x94CHO, xe2x80x94OR, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CONHR, xe2x80x94CONRRxe2x80x2, 
xe2x80x94NH2, xe2x80x94NHR, xe2x80x94N(R)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)2, xe2x80x94NHCOR, morpholino, nitro and xe2x80x94SO3H groups,
R and Rxe2x80x2 being chosen from C1-C6 alkyl groups and Ar being a C6-C14 aryl group,
R2 is chosen from nitro and xe2x80x94NHCOCF3 groups,
and the addition salts of these compounds with pharmaceutically acceptable acids.
A subject of the present invention is, more particularly, compounds chosen from the compounds of formula I and of formula II in which:
R1, R3 and R4 are chosen from hydrogen, halogens, hydroxyl, xe2x80x94CHO, xe2x80x94OR, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CONHR, xe2x80x94CONRRxe2x80x2, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94N(R)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)2, xe2x80x94NHCOR, morpholino, nitro and xe2x80x94SO3H groups,
R2 is chosen from nitro and xe2x80x94NHCOCF3 groups,
and the addition salts of these compounds with pharmaceutically acceptable acids.
In one preferred embodiment, a subject of the invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which R1 is chosen from hydrogen and methoxy and xe2x80x94N(CH3)2 groups and the compounds of formula II in which R1 is chosen from hydrogen and methoxy, N(CH3)2 and xe2x80x94NHCOCH3 groups and R2 is an xe2x80x94NHCOCF3 group, and the addition salts of these compounds with pharmaceutically acceptable acids.
In another form, a subject of the invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which R3 is a xe2x80x94COOEt group and the compounds of formula II in which R3 is a xe2x80x94COOEt group and R2 is chosen from xe2x80x94NHCOCF3 and xe2x80x94NO2 groups, and the addition salts of these compounds with pharmaceutically acceptable acids.
In another form, a subject of the invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which R4 is a methoxy group and the compounds of formula II in which R4 is a methoxy group and R2 is chosen from xe2x80x94NHCOCF3 and xe2x80x94NO2 groups, and the addition salts of these compounds with pharmaceutically acceptable acids.
The expression xe2x80x9caddition salts with pharmaceutically acceptable acidsxe2x80x9d denotes salts which give the biological properties of the free bases, without having an adverse effect. These salts may be, in particular, those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.
In general, the compounds of formulae I and II are obtained according the general reaction scheme described by Kitahara et al. (Chem Pharm. Bull 1994; 42: 1363-1364) and Kitahara et al. (Tetrahedron 1998; 54: 8421-8432). According to this scheme, the compounds of formula II may be prepared by a hetero Diels-Alder reaction between a quinoline-5,8-dione substituted in position 4 and a substituted aza-diene, followed by dehydrogenation of the intermediate dihydrogenated compound. The compounds of formula I are prepared from the compounds of formula II by cyclization: 